CN107353267B - A method of synthesis substituted furan - Google Patents
A method of synthesis substituted furan Download PDFInfo
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- CN107353267B CN107353267B CN201710591308.1A CN201710591308A CN107353267B CN 107353267 B CN107353267 B CN 107353267B CN 201710591308 A CN201710591308 A CN 201710591308A CN 107353267 B CN107353267 B CN 107353267B
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- alkynes
- substituted furan
- alcohol
- butanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/42—Singly bound oxygen atoms
Abstract
A method of synthesis substituted furan, Sonogashira coupling reaction occurs by idohydrocarbon and end alkynes butanol, intermediate product 3- alkynes -1- alcohol is generated, then Cyclization isomerization occurs under the action of Dess-Martin Periodinane and obtains 2- substituted furan class or 2, bis- substituted furan class compound of 5-.
Description
Technical field
The present invention relates to a kind of synthesis 2- substituted furan and 2, the method for bis- substituted furan of 5- passes through idohydrocarbon and end
Sonogashira coupling reaction occurs for alkynes butanol, generates 3- alkynes -1- alcohol, then the effect in Dess-Martin Periodinane
The lower method that Cyclization isomerization occurs and obtains a series of bis- substituted furan class compound of 2- substituted furans and 2,5-.
Background technique
Furans is a kind of relatively more extensive oxygen-containing five member ring heterocyclic compound of purposes, represents a kind of important molecular structure.
This structure is widely present among natural products and drug molecule, and the synthesis often as the heterocyclic compound of Various Complex is built
Block.The homologue of furans has very much, these product purposes are extensive, mostly the original of Medicine, pesticide, fragrance and chemical assistant
Material, it is external especially in recent years to develop a variety of newtype drugs containing furan nucleus, it is shown that good development prospect.Therefore, such as
What effectively synthesizes the project that substituted furan is always organic chemist's concern.Document also reports some effective conjunctions for many years
Method [James A.M.and at method, as cyclisation building furan nucleus occurs under metallic compound catalysis with connection ketenes
Gary S.B.,J.Org.Chem.,1994,59,7169-7171；Alexander S.D.and Vladimir G.P.,
Angewandte Chemie,2007,119(27),5287-5289]；Also useful 1,3-dicarbonyl compounds and alkynes carry out even
Then connection reaction realizes synthesis [Xin C., Xue X., the Lukasz W., et of furans in being catalyzed for metallic compound
A1., J.A.Chem.Soc., 2012,134 (49): 19981-19984.]；Exist also by 4- alkynes -2- hexene -1,6- glycol
A series of method that Cyclization isomerization coupling reaction generates furane derivatives occurs with isopropyl bromide under the catalysis of palladium chloride [to open small
Soldier, Fu Chunling, Ma Shengming, CN10185317A]；In addition there are also radical reaction is utilized, with metal as the catalyst to synthesis furan
It mutters and substituted furan, such as Mn (III) [Heiba E.A.I., Dessau R.M., J.Org.Chem., 1974,39 (23):
3456-3457.], there is also Ce (IV), Co (II), Pd, Sd and Mo etc..Either classical method is still new in recent years
The method of development finally requires greatly to carry out cyclization under the catalysis of metallic compound to realize the building of furan nucleus, raw
Cost is produced to improve, post-reaction treatment is complicated, and the prospect of the industrialized production of reaction is thus by considerable degree of limitation, therefore,
Development can construct the synthesis of furan nucleus from raw material simple and easy to get in the case where not needing metal compound as catalyst effect
New method is just particularly important.
Summary of the invention
The object of the present invention is to provide a kind of to be set out by raw material simple and easy to get and synthesizes 2- substituted furan and 2,5- bis- takes
For the method for furfuran compound.Synthesis 2- substituted furan provided by the invention and 2, the method for bis- substituted furan of 5-, is to pass through
Sonogashira coupling reaction occurs for idohydrocarbon and end alkynes butanol, generates intermediate product 3- alkynes -1- alcohol, then in Dess-
A series of bis- substituted furan class compound of 2- substituted furans and 2,5- is obtained under the action of Martin Periodinane.Reaction equation
It is as follows:
R1=alkyl, aryl；R2=H, alkyl, aryl；It the steps include:
(1) idohydrocarbon I and the alkynes butanol II of end be in triethylamine, in two triphenylphosphine palladium of dichloro and cuprous iodide
Under effect, Sonogashira coupling reaction occurs and generates intermediate product 3- alkynes -1- alcohol III；Then at room temperature, nitrogen protection,
Raw material II I and Dess-Martin Periodinane are added in reaction flask, CH2Cl2For solvent, react 0.5~6 hour,
After fully reacting, saturated sodium bicarbonate solution is added and is quenched, ether extraction, saturated brine washing, anhydrous sodium sulfate is dry, mistake
Filter, concentration, column chromatography obtain product 2- substituted furan or 2, bis- substituted furan IV of 5-, and yield is 53~80%.
(2) raw material proportioning are as follows: idohydrocarbon I: end alkynes butanol II: two triphenylphosphine palladium of dichloro: cuprous iodide: three
Ethamine=1 mM: 1.2 mMs: 0.02 mMs: 0.01 mM: 0.5 milliliters~3 milliliters.
(3) raw material proportioning are as follows: 3- alkynes -1- alcohol III:Dess-Martin Periodinane: methylene chloride=1 milli
Mole: 1.5 mMs: 5~20 milliliters.
End alkynes butanol II of the invention is primary alconol, secondary alcohol；The 3- alkynes 1- alcohol III of generation is primary alconol, secondary alcohol.
The present invention relates to a kind of 2- substituted furan and 2, the synthetic method of bis- substituted furan class compound of 5- overcomes tradition
The drawbacks of method, has the advantage that 1) this method is easy to operate, and raw materials and reagents are easy to get；2) reaction condition is mild, yield compared with
It is high；3) 2- and 5- bit substituent can be introduced simultaneously；4) product can be easily separated purifying.
Made by 3- alkynes -1- alcohol in Dess-Martin Periodinane the innovation of the invention consists in that having developed one kind
2- substituted furan and 2 is synthesized with lower direct Cyclization isomerization, the method for bis- substituted furan class compound of 5- is compared with other methods,
This method final step realizes under conditions of no metallic catalyst, merely with Dess-Martin Periodinane from
And cyclisation occurs and obtains furan nucleus.
Specific embodiment
Embodiment 1
Two triphenylphosphine palladium (14mg, 0.02mmol) of dichloro, cuprous iodide is added in the reaction flask dry to one
(1.9mg, 0.01mmol), triethylamine (2ml), iodobenzene (204mg, 1mmol), 3- butyne-1-ol (84mg, 1.2mmol), 50 DEG C
Lower reaction 3 hours is stirred 0.5 hour with the ethyl acetate of 1:1 and the mixed solution quenching reaction of water, and water layer is extracted with ether,
Merge organic layer, organic layer is washed with saturated brine, and anhydrous sodium sulfate is dry, filters, is spin-dried for, rapid column chromatography (mobile phase: stone
Oily ether/ethyl acetate=10:1), obtain intermediate product 4- phenyl -3- butyne-1-ol 134mg, yield 92%.In 4- phenyl -3-
Be added in butyne-1-ol 73mg (0.5mmol) 5ml dichloroethanes and Dess-Martin Periodinane (318mg,
0.75mmol), nitrogen protection, stirring 1 hour, saturated sodium bicarbonate quenching reaction, ether extract 3 times at room temperature, saturated brine
Organic phase is washed, anhydrous sodium sulfate is dry, rapid column chromatography (mobile phase: petroleum ether), and revolving removes solvent, obtains colourless liquid
Product 2- benzofurane 52mg, yield 72%.
1H NMR (400MHz, CDCl3) δ 7.73~7.65 (m, 2H), 7.52~7.46 (J=1.1Hz, 1H) 7.41~
7.35 (J=7.7Hz, 2H), 7.29~7.24 (m, 1H), 6.70~6.64 (d, J=3.3Hz, 1H), 6.53~6.43 (dd, J
=3.4,1.8Hz, 1H)；13CNMR (75MHz, CDCl3) δ 153.3,149.1,132.5,127.6,125.8,122.3,114.6,
111.2；
HRMS-ESI calcd for C10H8O[M+H]+:: 145.0653, found:145.0648
Embodiment 2
Two triphenylphosphine palladium (35mg, 0.01mmol) of dichloro, cuprous iodide is added in the reaction flask dry to one
(4.8mg, 0.025mmol), triethylamine (10ml), iodobenzene (510mg, 2.5mmol), 4- pentyne -2- alcohol (252mg, 3mmol),
It reacts 40 minutes at 45 DEG C, with the ethyl acetate of 1:1 and the mixed solution quenching reaction of water, stirs 0.5 hour, water layer ether
Extraction merges organic layer, and organic layer is washed with saturated brine, and anhydrous sodium sulfate is dry, filters, is spin-dried for, rapid column chromatography (flowing
Phase: n-hexane/ethyl acetate=10:1), obtain faint yellow oil product 5- phenyl -4- pentyne -2- alcohol 390mg (97.5%).
10ml dichloroethanes and Dess- are added in obtained intermediate product 5- phenyl -4- pentyne -2- alcohol 390mg (2.5mmol)
MartinPeriodinane (1.48g, 3.5mmol), nitrogen protection, reacts 2.5 hours at room temperature, and TLC detects fully reacting,
Saturated sodium bicarbonate quenching reaction, ether extract 3 times, and saturated brine washs organic phase, and anhydrous sodium sulfate is dry, rapid column chromatography
(mobile phase: petroleum ether) obtains colorless liquid product 2- methyl -5- benzofurane 268mg, yield 67.8%.1H NMR
(400MHz, CDCl3) δ 7.73~7.65 (dd, J=8.2,1.0Hz 2H), 7.47~7.38 (m, 2H) 7.31~7.22 (m,
1H), 6.62~6.56 (d, J=3.2Hz, 1H), 6.13~6.07 (d, J=3.2Hz, 1H), 2.44~2.39 (s, 3H)；13CNMR (75MHz, CDCl3) δ 152.3,151.9,131.2,128.6,126.8,123.3,107.6,105.8,13.7；
HRMS-ESI calcd for C11H10O[M+H]+:: 159.0810, found:159.0804
Embodiment 3
Two triphenylphosphine palladium (35mg, 0.01mmol) of dichloro, cuprous iodide is added in the reaction flask dry to one
(4.8mg, 0.025mmol), triethylamine (10ml), 4- methoxyl group iodobenzene (585mg, 2.5mmol), 4- pentyne -2- alcohol (252mg,
3mmol), it reacts 40 minutes at 70 DEG C, with the ethyl acetate of 1:1 and the mixed solution quenching reaction of water, stirs 0.5 hour, water
Layer is extracted with ether, merges organic layer, and organic layer is washed with saturated brine, and anhydrous sodium sulfate is dry, filters, is spin-dried for, quick column
It chromatographs (mobile phase: petrol ether/ethyl acetate=6:1), obtains colorless oil as product 5- (4- methoxyl group) phenyl -4- pentyne -2-
Alcohol 435mg, yield 91.6%.10ml dichloroethanes and Dess-Martin are added in product 380mg (2.0mmol)
Periodinane (1.27g, 3mmol), nitrogen protection at 80 DEG C stir 4 hours, saturated sodium bicarbonate quenching reaction, ether extraction
It takes 3 times, saturated brine washs organic phase, and anhydrous sodium sulfate is dry, rapid column chromatography (mobile phase: petroleum ether), and it is solid to obtain white
Body object 2- methyl -5- (4- methoxyl group) benzofurane 280mg, yield 74.6%.1H NMR (400MHz, CDCl3) δ 7.57~
7.55 (d, J=8.5Hz 2H), 6.91~6.89 (d, J=8.5Hz, 2H), 6.40~6.39 (d, J=3.2Hz, 1H), 6.03
~6.01 (d, J=3.3Hz, 1H), 3.78 (s, 3H), 2.35 (s, 3H)；13CNMR (101MHz, CDCl3) δ 158.66,151.2,
149.5,124.7,124.6,114.1,107.5,104.2,55.3,13.5；HRMS-ESI calcd for C12H12O2[M+H]+::
189.0915, found:189.0911
Embodiment 4
Addition two triphenylphosphine palladium (70mg, 0.1mmol) of dichloro in the reaction flask dry to one, cuprous iodide (10mg,
0.05mmol), triethylamine (20ml), 4- nitro iodobenzene (1.25g, 5mmol), 4- pentyne -2- alcohol (0.45g, 5.35mmol), 60
It reacts 30 minutes at DEG C, with the ethyl acetate of 1:1 and the mixed solution quenching reaction of water, stirs 0.5 hour, water layer is extracted with ether
It takes, merges organic layer, organic layer is washed with saturated brine, and anhydrous sodium sulfate is dry, filters, is spin-dried for, rapid column chromatography (flowing
Phase: petrol ether/ethyl acetate=10:1), obtained product 5- (4- nitro) phenyl -4- pentyne -2- alcohol 0.91g, yield
88.7%.It takes and 20ml dichloroethanes and Dess-Martin Periodinane is added in product 570mg (3.0mmol)
(1.7g, 4mmol), nitrogen protection, is stirred 5 hours, saturated sodium bicarbonate quenching reaction at room temperature, and ether extracts 3 times, saturated salt
Water washing organic phase, anhydrous sodium sulfate is dry, and rapid column chromatography (mobile phase: petroleum ether) obtains yellow oil 2- methyl -5-
(4- nitro) benzofurane 326mg, yield 53.5%.1H NMR (400MHz, CDCl3) δ 8.23~8.21 (d, J=8.1Hz,
2H), 7.72~7.74 (d, J=8.1Hz, 2H), 6.78~6.77 (d, J=3.4Hz, 1H), 6.15~6.14 (d, J=
3.4Hz, 1H), 2.41 (s, 3H)；13CNMR (101MHz, CDCl3) δ 154.66,150.13,136.73,124.37,124.09,
123.27,110.29,108.82,13.88；HRMS-ESI calcd for C11H9NO3[M+H]+:: 204.0660, found:
204.0656
Claims (2)
1. a kind of method for synthesizing substituted furan, it is characterised in that Sonogashira occurs by idohydrocarbon and end alkynes butanol
Coupling reaction generates intermediate product 3- alkynes 1- alcohol, then Cyclization isomerization occurs under the action of Dess-Martin Periodinane
Obtain 2- substituted furan class or 2, bis- substituted furan class compound of 5-, reaction equation is as follows:
R1=alkyl, aryl；R2=H, alkyl, aryl；It the steps include:
(1) idohydrocarbon I and the alkynes butanol II of end are in triethylamine, in the effect of two triphenylphosphine palladium and cuprous iodide of dichloro
Under, Sonogashira coupling reaction occurs and generates intermediate product 3- alkynes -1- alcohol III；Then at a certain temperature, nitrogen protection,
Raw material II I and Dess-Martin Periodinane are added in reaction flask, CH2Cl2For solvent, react 0.5~6 hour,
After fully reacting, saturated sodium bicarbonate solution quenching reaction is added, ether extraction, saturated brine washing, anhydrous sodium sulfate is dry,
Filtering, concentration, rapid column chromatography obtain product 2- substituted furan or 2, bis- substituted furan IV of 5-；
(2) raw material proportioning are as follows: idohydrocarbon I: end alkynes butanol II: two triphenylphosphine palladium of dichloro: cuprous iodide: triethylamine
=1 mM: 1.2 mM: 0.02 mM: 0.01 mM: 0.5 milliliter~3 milliliters；
(3) raw material proportioning are as follows: 3- alkynes -1- alcohol III:Dess-Martin Periodinane: methylene chloride=1 mM:
1.5 mMs: 5~20 milliliters.
2. synthesis 2- substituted furan class according to claim 1 and 2, the method for bis- substituted furan of 5-, it is characterized in that described
End alkynes butanol II be primary alconol, secondary alcohol；The 3- alkynes 1- alcohol III of generation is primary alconol, secondary alcohol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0521373A1 (en) * | 1987-06-23 | 1993-01-07 | Givaudan-Roure (International) S.A. | Method for preparing dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan |
| CN101805317A (en) * | 2010-03-25 | 2010-08-18 | 浙江大学 | Method for synthesizing polysubstituted furan compounds |
| CN105324030A (en) * | 2013-06-28 | 2016-02-10 | 阿彻丹尼尔斯米德兰德公司 | Tetrahydrofuran-2,5-dicarbaldehydes (diformyl-tetrahydrofuran, DFTHF) and process for making the same |
-
2017
- 2017-07-19 CN CN201710591308.1A patent/CN107353267B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0521373A1 (en) * | 1987-06-23 | 1993-01-07 | Givaudan-Roure (International) S.A. | Method for preparing dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan |
| CN101805317A (en) * | 2010-03-25 | 2010-08-18 | 浙江大学 | Method for synthesizing polysubstituted furan compounds |
| CN105324030A (en) * | 2013-06-28 | 2016-02-10 | 阿彻丹尼尔斯米德兰德公司 | Tetrahydrofuran-2,5-dicarbaldehydes (diformyl-tetrahydrofuran, DFTHF) and process for making the same |
Non-Patent Citations (1)
| Title |
|---|
| A new synthesis of 3-carboxy-2,5-disubstituted furans and their conversion to 5-vinyl derivatives;James A. Marshall et al.;《Tetrahedron Letters》;20001231;第41卷;第1347-1350页 * |
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